The lack of regeneration in the adult mammalian central nervous system can be attributed, at least[unreadable] in part, to inhibitors of regeneration in myelin. To date 3 inhibitors have been identified and all 3[unreadable] interact with the same receptor complex to effect inhibition. However, if neuronal cAMP is elevated,[unreadable] inhibition by myelin is blocked and regeneration is promoted in vivo. This cAMP effect is[unreadable] transcription-dependent and two genes that are up regulated are metallothionein-l/ll (MT-I/II) and[unreadable] secretory leukocyte protease inhibitor (SLPI). If added to neurons in culture, either of these two[unreadable] proteins allows neurons to grow on myelin. The immediate goals of the studies in this proposal are[unreadable] to a) Characterize and optimize the ability of MT-1/2 and SLPI to overcome myelin inhibitors in[unreadable] culture, b) Begin to address their mechanism of action by asking if they block the signal[unreadable] transduction pathway initiated by myelin inhibitors, c) Optimize conditions for in vivo delivery by[unreadable] assessing if neurons from animals treated with MT-1/2 or SLPI can grow in an inhibitory[unreadable] environment when cultured, and d) Determine if either MT-1/2 or SLPI can encourage dorsal[unreadable] column regeneration in vivo. The long-term objective is to determine if either MT-1/2 or SLPI can be[unreadable] developed as a therapy for patients with spinal cord injury.